Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.CN([CH:18]=[O:19])C>>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:18]=[O:19])=[CH:7]1
Reactant: CN(C)C=O
Reactant: c1ccc2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a 500 mL round bottom flask containing 250 mL of DMF at 0° C. was added 105 mL (1.12 mol) of phosphorous oxychloride dropwise via an addition funnel. The reaction mixture was stirred for 30 min at 0° C. and then indole (0.51 mol) was added as a solid. The reaction mixture was heated to 80° C. for 6 h and then cooled in an ice bath. The cold solidified reaction was quenched with water (˜2 L) until all the solid had dissolved. The solution was kept cool and the pH was adjusted to ˜11 by the addition of 50% NaOH. The precipitate was filtered and washed with water. The filter cake was dried in vacuo in the presence of P2O5 to yield crude indole-3-carboxaldehyde (90-95% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]=O)[CH2:3][CH2:2]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1.[Ni]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=CCCN1CCOCC1
Agent: [Ni]
Solvent: C1COCCO1
Product: C1CCN(CCCN2CCOCC2)C1

Procedure:
143 g (1 mol) of 3-morpholinopropionaldehyde in 143 g of dioxane are pumped into 71 g (1 mol) of pyrrolidine and 40 g of Raney nickel at 120° C. and hydrogenated at 160 bar. The reaction mixture is suction filtered, concentrated by evaporation and distilled. B.p. 0.1 : 82° C., purity according to gas chromatogram: 94.5%. Yield: 51 g; molar mass found: 196 v. the molecular weight calculated for C11H22N2O: 198.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].C(C1C=CC([CH:20]([O:24]C(C2C=CC(C#N)=CC=2)C2OC2)[CH:21]2[O:23][CH2:22]2)=CC=1)#N.[OH-].[CH2:38]([N+:45](C)(C)C)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:2]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:22][CH:21]([OH:23])[CH2:20][O:24][C:42]1[CH:43]=[CH:44][C:39]([C:38]#[N:45])=[CH:40][CH:41]=1)(=[O:3])[CH3:1]
Reactant: N#Cc1ccc(C(OC(c2ccc(C#N)cc2)C2CO2)C2CO2)cc1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: [OH-]
Product: CC(=O)c1c(O)cccc1OCC(O)COc1ccc(C#N)cc1

Procedure:
A solution of 2,6-dihydroxyacetophenone (15.2 g), p-cyanophenylglycidyl ether (17.5 g) and benzyltrimethylammonium hydroxide (10 drops of a 40% solution) was heated under reflux for 2 days. The solvent was then removed by evaporation under reduced pressure to give 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-p-cyanophenoxypropane, 28.4 g, as a beige solid. A portion was recrystallized from ethanol affording cream prisms m.p. 157°-158°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[NH2:5].N1C2C(=CC=CC=2)[C:14](=[O:15])[C:12]1=[O:13].Cl.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>>[OH:9][C:8]1[C:2]([CH3:1])=[C:3]2[C:4](=[CH:6][C:7]=1[CH3:10])[NH:5][C:12](=[O:13])[C:14]2=[O:15].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][N:31]=[C:14]2[C:6]3[C:4](=[CH:3][C:2]([CH3:1])=[C:8]([OH:9])[C:7]=3[CH3:10])[NH:5][C:12]2=[O:13])=[CH:26][CH:25]=1
Reactant: Cc1ccc(NN)cc1
Reactant: Cc1cc(N)cc(C)c1O
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Product: Cc1cc2c(c(C)c1O)C(=O)C(=O)N2
Product: Cc1ccc(NN=C2C(=O)Nc3cc(C)c(O)c(C)c32)cc1

Procedure:
5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione was prepared from 3,5-dimethyl-4-hydroxyaniline according to Procedure A: 1H NMR (DMSO-d6): δ 2.17 (s, 3H), 2.30 (s, 3H), 6.45 (s, 1H), 8.29 (s, 1H), 10.65 (s, 1H); ESI-MS m/z 190 (M−H)−. The isatin was combined with 4-methylphenylhydrazine hydrochloride according to Procedure H to provide the title compound in 41% yield. 1H NMR (DMSO-d6): δ 2.15 (s, 3H), 2.24 (s, 3H), 2.43 (s, 3H), 6.46 (s, 1H), 7.16 (m, 4H), 7.88 (s, 1H), 10.64 (s, 1H), 12.85 (s, 1H). APCI-MS m/z 294 (M−H, 45%).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:21][C:22]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH:1]1([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([NH:21][C:22]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]3)=[O:11])=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(N)CC1
Reactant: O=C(O)c1ccc(OC2CC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2ccc(OC3CC3)cc2)CC1
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a 0° C. suspension of 4-cyclopropoxybenzoic acid (24.5 g, 137.3 mmol) in dichloromethane (350 mL) containing 2 drops of DMF, slowly add oxalyl chloride (23.8 mL, 274.7 mmol). After addition, remove the cooling bath and stir for 2 hours. Concentrate the material to dryness under reduced pressure. Dissolve the residue in dichloromethane (500 mL), and then add ethyl 1-aminocyclopropanecarboxylate hydrochloride (Indofine #04-265, 24.9 g, 150.5 mmol) and triethylamine (57.2 mL, 410.4 mmol). Stir the mixture at ambient temperature for approximately 16 hours. Wash the mixture once with 10% NaHSO4 (250 mL). Separate the organic portion and extract the aqueous portion 2× with dichloromethane (200 mL). Combine the organic, dry over sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography (0% to 45% EtOAc/Hex) to give the title compound (33.7 g, 85%): MS (m/z): 290 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[CH3:12][C:13](=O)[CH3:14].N1CCCC1>C1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:13]([CH3:14])([CH3:12])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccc(F)cc1O
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC1(C)CC(=O)c2ccc(F)cc2O1
Temperature: 80 °C
Yield: 70.7 %

Procedure:
To 1-(4-fluoro-2-hydroxyphenyl)ethanone (5.75 g, 37.3 mmol) and propan-2-one (12 mL, 37.3 mmol) in benzene (50 mL) was added pyrrolidine (3.11 mL, 37.3 mmol) and the reaction heated at 80° C. for 3 hours. The reaction was diluted with ethyl acetate (50 mL), washed with 1N HCl (50 mL), brine (50 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate, to provide the title compound (5.12 g, 70.7% yield).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[C:6]([NH:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1.ClC1C2C(=C(C(F)(F)F)C=CC=2)N=CC=1.NC1C=C(C(F)(F)F)C=CC=1C(O)=O.S(Cl)(Cl)=O.[NH2:63][CH:64]1[CH2:69][CH2:68][CH2:67][N:66]([CH2:70][CH3:71])[CH2:65]1>>[CH2:70]([N:66]1[CH2:67][CH2:68][CH2:69][CH:64]([NH:63][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([C:3]([F:29])([F:28])[F:2])=[CH:5][C:6]=2[NH:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:65]1)[CH3:71]
Reactant: CCN1CCCC(N)C1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: Cl
Agent: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: Nc1cc(C(F)(F)F)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCN1CCCC(NC(=O)c2ccc(C(F)(F)F)cc2Nc2ccnc3c(C(F)(F)F)cccc23)C1

Procedure:
4-Trifluoromethyl-2-(8-trifluoromethyl-4-quinolylamino)benzoyl chloride hydrochloride prepared by reaction of 4-chloro-8-trifluoromethyl quinoline with 2-amino-4-trifluoromethylbenzoic acid and treatment of the reaction product with thionyl chloride, is reacted with 3-amino-1-ethylpiperidine to form the title compound.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>ClCCl.O1CCOCC1>[CH3:17][O:16][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:18])=[O:5])[CH2:13][CH2:12]1)=[O:15]
Reactant: COC(=O)C1CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylate (3.0 g, 12 mmol) in dichloromethane (9 mL) was added hydrochloric acid in 1,4-dioxane (4 M) and stirred at ambient temperature for 24 h. The final product was formed as a white solid, which was washed with ether and filtered (2.3 g). 1H NMR (400 MHz, DMSO-d6) δ 4.09 (s, 2H), 3.64 (s, 3H), 3.46 (br. s., 2H), 3.11 (br. s., 2H), 2.67 (br. s., 1H), 1.82-2.12 (m, 4H)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:21][C:22]([OH:24])=[O:23])[CH2:11][CH2:12][N:13]2[CH2:18][C:17](=[O:19])[O:16][C:15](=[O:20])[CH2:14]2)[CH2:5][C:4](=[O:25])[O:3]1.[OH2:26].C(N(CC)CC)C.[CH2:34]([O:36][C:37](=[O:49])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH3:35]>CN(C)C=O>[C:15]([CH2:14][N:13]([CH2:12][CH2:11][N:10]([CH2:21][C:22]([OH:24])=[O:23])[CH2:9][CH2:8][N:6]([CH2:7][C:2](=[O:1])[NH:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:49])[CH2:5][C:4]([OH:3])=[O:25])[CH2:18][C:17]([OH:16])=[O:19])([OH:20])=[O:26]
Reactant: O=C(O)CN(CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Reactant: O
Reactant: CCOC(=O)CCCCCCCCCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCCCCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
17.85 g (50 mmol) of 1.5-bis(2,6-dioxomorpholino)-3-carboxymethyl-3-azapentane is stirred in 200 ml of dimethylformamide and mixed with 9 ml (50 mmol) of water. The solution is heated for 3 hours to 70° C., cooled off to 0° C. and 36.07 ml (260 mmol) of triethylamine and 10.8 g (50 mmol) of 11-aminoundecanoic acid ethyl ester are added. After stirring overnight at room temperature, the solution is evaporated to dryness in a vacuum. The residue is taken up in 100 ml of water and the solution is mixed by drops with concentrated hydrochloric acid until permanent cloudiness. After stirring overnight in the ice bath, the finely crystalline precipitate is suctioned off, washed with water and dried in a vacuum at 50° C. 14.9 g (65% of theory) of the title compound is obtained as a white powder with melting point 155-157° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15](=[O:22])[CH:16]([C:18]([F:21])([F:20])[F:19])[OH:17].C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([CH:39]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=2)[N:40]2[CH2:41][CH2:42][N:43]([C:2]([O:17][CH:16]([C:15]([O:14][CH3:13])=[O:22])[C:18]([F:21])([F:20])[F:19])=[O:4])[CH2:44][CH2:45]2)=[CH:47][CH:48]=1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: COC(=O)C(O)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Reaction time: 2 h
Yield: 140.3 %

Procedure:
To a stirring solution of triphosgene (65 mg, 0.22 mmol) in CH2Cl2 (5.0 mL) was added methyl-3,3,3-trifluoro-DL-lactate (116 mg, 0.73 mmol) followed by N,N-diisopropylethylamine (0.38 mL, 2.19 mmol). After 2 h, 1-(bis(4-chlorophenyl)methyl)piperazine (160 mg, 0.50 mmol) was added as a solution in CH2Cl2 (2 mL) and stirred for another 2 h. The mixture was concentrated under reduced pressure and purified directly by SiO2 flash chromatography (25% EtOAc/hexanes) to provide the titled compound (156 mg, 62%): 1H NMR 500 MHz (CDCl3) δ 7.31 (d, J=8.47 Hz, 4H), 7.26 (d, J=8.41 Hz, 4H), 5.43 (q, J=7.03 Hz, 1H), 4.23 (s, 1H), 3.85 (s, 3H), 3.66-3.46 (m, 4H), 2.44-2.32 (m, 4H); HRMS m/z calc'd for [M+H]+ C22H21Cl2F3N2O4: 505.0903. found 505.0905.
Reaction SMILES: [H-].[Na+].CO[C:5](=O)[CH2:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:11]=2[CH:10]=1)=[O:8].C([O:25][C:26](=[O:29])CBr)C.C(O)(=O)C>O1CCCC1.O>[CH3:19][O:18][C:16]1[C:15]([O:20][CH3:21])=[CH:14][C:12]2[S:13][C:9]([C:7](=[O:8])[CH2:6][CH2:5][C:26]([OH:29])=[O:25])=[CH:10][C:11]=2[CH:17]=1
Reactant: COC(=O)CC(=O)c1cc2cc(OC)c(OC)cc2s1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2cc(C(=O)CCC(=O)O)sc2cc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion in oil, 1.37 g) in dry tetrahydrofuran (15 ml) was stirred at room temperature under an atmosphere of nitrogen and treated dropwise over 10 min. with a solution of 3-(5,6-dimethoxybenzo[b]thien-2-yl)-3-oxo-propanoic acid methyl ester (5.0 g) in dry tetrahydrofuran (75 ml). After 30 min. ethylbromoacetate (4.0 ml) was added and the reaction mixture was stirred at room temperature for a further 45 min. and then warmed to 40° C. After 2 hours the suspension was cooled, treated with glacial acetic acid (2 ml) then poured into water (400 ml). The mixture was extracted with diethyl ether (2×100 ml), the organic extracts were combined, washed with water (50 ml), dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in ethanol (25 ml), 5M hydrochloric acid (50 ml) was added and then the solution was heated at reflux for 10 hours. The resultant white suspension was cooled to room temperature and treated dropwise with 10M potassium hydroxide (30 ml). The reaction mixture was then stirred and heated at reflux under an atmosphere of nitrogen. After 1 hour the solution was cooled, diluted with water (100 ml) and extracted with ethyl acetate (50 ml). The aqueous layer was separated, stirred and acidified with 5M hydrochloric acid (10 ml). The resultant precipitate was filtered off, washed with water and dried at 65° C. under vacuum to give 4-(5,6-dimethoxy-benzo[b]thien-2-yl)-4-oxo-butanoic acid as a pale yellow solid (4.68 g). A portion crystallized from dichloromethane/methanol had m.p. 177°-178° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1CCCCC1.C(O)C>[CH2:17]([NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:29][CH:28]=1)=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1c(C(=O)NCc2ccccc2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)NCc2ccccc2)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (54 mg, 0.25 mmol), 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid benzylamide (63.5 mg, 0.2625 mmol) and piperidine (2 drops) in ethanol (0.5 mL) was stirred at room temperature for 7 days. The precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@H:10](C(O)=O)[CH2:11][CH2:12][C:13](=[O:15])[NH2:14].C>O1CCOCC1>[N-:14]=[C:13]=[O:15].[CH3:4][O:3][C:2](=[O:1])[C@H:10]([CH2:11][CH2:12][C:13](=[O:15])[NH2:14])[NH2:9]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)CC[C@H](N)C(=O)O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CCC(N)=O
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of glutamine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give glutamine methyl ester isocyanate.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>>[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
The largest amount of silica gel that still allowed the resulting slurry to be stirred magnetically at 0° C., was added to conc. sulfuric acid (125 ml). To this mixture 4-fluorobenzonitrile (12.5 g, 103 mmol) was added followed by potassium nitrate (10.4 g, 103 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. The sulfuric acid was removed from the product by passing the mixture through a short column of silica gel and the product was washed out with methylene chloride. The solvent was evaporated to leave the product as a crystalline solid. Yield 6.0 g, mp 86°-88° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCCCOc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 134A (465 mg) and 1-(3-bromopropoxy)naphthalene (431 mg) in N,N-dimethylformamide (10 ml) was added cesium carbonate (1059 mg). The reaction was stirred at room temperature overnight and diluted with ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by RPHPLC to provide ethyl 3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-D6) δ 8.13 (d, J=7.98 Hz, 1H), 7.85 (d, J=7.67 Hz, 1H), 7.74 (dd, J=9.21, 4.30 Hz, 1H), 7.42-7.58 (m, 3H), 7.37 (t, J=7.98 Hz, 1H), 7.27 (dd, J=8.90, 2.45 Hz, 1H), 7.10-7.20 (m, 1H), 6.85 (d, J=7.36 Hz, 1H), 4.87 (t, J=6.90 Hz, 2H), 4.14 (t, J=5.83 Hz, 2H), 2.21-2.39 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: COc1cnc(-c2ccccn2)nc1Cl
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2nc(-c3ccccn3)ncc2OC)c1

Procedure:
The title compound was prepared from 4-chloro-5-methoxy-2-(2-pyridinyl)pyrimidine (100 mg, 0.451 mmol) and m-anisidine (51 μl, 0.451 mmol) similar to Example 13 and isolated as a tan oily liquid (63 mg, 45%). 1H NMR (CDCl3): 8.76–8.74 (m, 1H), 8.37 (dd, J=1.1, 8.0 Hz, 1H), 8.05 (s, 1H), 7.79–7.73 (m, 2H), 6.65–6.62 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][CH2:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCCCl)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
4-Fluorophenol (8.92 mmol) and 1-chloro-2-bromoethane (13.4 mmol) were dissolved in acetone (18 mL). The solution was added with potassium carbonate (12.5 mmol) and heated under reflux for 10 hours. The mixture was allowed to cool to room temperature and then filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (yield: 31%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=O)=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:61]2[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]2)=[O:40])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reactant: CN1CCNCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 74.7 %

Procedure:
A solution of 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[2-(5-carboxypent-1-yloxy)-4-methylphenyl]benzamide (3.5 g) in ethyl acetate (30 ml) was treated at ambient temperature with triethylamine (575 mg), N-methylpiperazine (569 mg), and diphenylphosphoryl azide (1.56 g). The reaction mixture was stirred at the same temperature for 17 hours. The reaction mixture was washed with brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (SiO2 100 g, 3% methanol in chloroform) to give 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (2.93 g).